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Neuromuscular Blocking Agents
Click here for an index of neuromuscular blocking agents. This article is under construction. I do love NMBs though. I'm trying to make this into a category so I can put like SCh and dTC and stuff in it. Everything in blue text has been copied from my new site The Art of Paralytics. Learning about NMBs: Some of the most fascinating chemicals known are neuromuscular blocking agents (also called NMBs, neuromuscular blockers and neuromuscular blocking drugs). Only a few milligrams of a NMB can completely paralyze a human like you. Today, they're used every day in surgeries to prevent movement of the patient during an operation, and they're useful in any other sort of situation where movement would be more harmful than helpful. If you've ever had surgery under general anesthesia, there's an excellent chance that you once had a neuromuscular blocking agent in your bloodstream. Congratulations! You've survived one of the most dangerous molecules in the world. If you've never heard of neuromuscular blocking agents before and accidentally clicked on this huge list of NMBs , the sheer number of them probably seemed overwhelming. You don't have to go through and memorize every single one on the list right off the bat. If you are new and want to start learning about specific NMBs, the best ones to start out with are d-tubocurarine and succinylcholine. D-tubocurarine was the first NMB ever discovered, and other NMBs were designed to mimic its effects. Succinylcholine has a slightly different mechanism of action than all the other NMBs, and it is also one of the most well-known and widely used NMBs today. If you're already familiar with NMBs, then feel free to use this as a review or to learn something new. General Facts to Know: Neuromuscular blocking agents quickly cause paralysis of every single voluntary muscle in the body when they are given. This includes the diaphragm and intercostal muscles, which are needed to be able to breathe. If a neuromuscular blocking agent is given to someone and you don't want the person to die, the person will need to be given artificial respiration until the NMB wears off. Death by NMB is not a pleasant way to go. While under the influence of a neuromuscular blocking agent, a person is still fully conscious and is able to think and be aware everything that goes on around them. NMBs do not affect the brain in any way, mainly because these molecules are polar and don't cross the blood brain barrier and also do absolutely nothing to reduce pain. All they do is make the person unable to move. And that's it. It is recommended that you do not give a person a neuromuscular blocking agent while they're awake unless you absolutely need to. Such an experience can be extremely frightening to the person receiving the NMB. Basic Mechanism of Action (how they work): When you wish to make a normal voluntary movement, an action potential, which is a change in voltage between the inside and outside of the nerve that propagates down the nerve (you can think of it as an electrical signal), is usually generated in the brain. It then travels out of your brain and down your spinal cord, and from there, it goes out to the ends of some of your peripheral nerves. Your voluntary muscles are conveniently located right next to the ends of these peripheral nerves, which communicate information to the muscle. However, although the nerves and their associated muscles are very close together, they are not directly touching. Instead, there is a tiny gap, or synapse, between the two. This space where the nerve and muscle "meet" is called the neuromuscular junction. In order for muscle contraction to occur, the nerve must send some kind of message across the synapse to be able to communicate with the muscle. In motor neurons, this is done through the release of the neurotransmitter acetylcholine. Inside the ends of your neurons, you have many small little bubbles called vesicles, and each vesicle holds around 5,000-10,000 molecules of acetylcholine waiting to be released. When the action potential reaches the end of the nerve, voltage gated calcium channels on your nerve terminals open and let calcium into the nerve. This triggers a sequence of events involving several proteins that are activated by calcium, which eventually leads to the vesicles containing acetylcholine fusing with the membrane of the neuron and releasing the acetylcholine into the neuromuscular junction. The acetylcholine then crosses the synaptic cleft, the area of space between the neuron and the muscle, and reaches the muscle. Now, on the surface of your muscle cells, you have a whole bunch of acetylcholine receptors on the motor end plate, which is right across from the nerve in the NMJ. These receptors are also ion channel proteins, and they open when acetylcholine binds to them. So acetylcholine binds to the acetylcholine receptors, and the receptors open and let positively charged sodium ions into the muscle, raising the voltage inside. This is called depolarization, and when enough acetylcholine molecules bind to their receptors, the voltage becomes high enough to trigger an action potential that further spreads across the muscle, eventually leading to muscle contraction. Remember the part just now where acetylcholine bound to the acetylcholine receptors on the muscles? This is where the neuromuscular blockers like to mess things up. You see, neuromuscular blocking molecules also like to bind to acetylcholine receptors. They're able to do this because certain parts of their molecules (specifically the quaternary ammonium or N+) are similar in appearance to acetylcholine. Those parts of the molecules are able to effectively mimic acetylcholine and fit in the same spot on the receptor that acetylcholine would. Unlike acetylcholine, however, most neuromuscular blocking agents (non-depolarizing NMBs) do not cause the receptor to open when they bind, so the receptor stays closed, and acetylcholine can't bind to it to open it since the NMB molecule is there instead. As a result, no sodium will be able to enter the muscle through the ACh receptors to depolarize it, an action potential will not be generated, and you don't move. Neuromuscular blockers that keep the ACh receptor closed when they bind to it and don't allow depolarization to occur in the muscle are called non-depolarizing. The vast majority of NMBs used today are non-depolarizing. However, succinylcholine is one neuromuscular blocking agent that is an exception to this. Instead of blocking the acetylcholine receptors, it opens them, causes depolarization, and then kind of just stays there and holds them open. Normally, when acetylcholine binds to its receptors and causes a depolarization, it is immediately broken down by an enzyme called acetylcholinesterase, allowing the receptors to close and the membrane to repolarize again. In order to have muscle contraction, you actually have to send hundreds of action potentials to your muscle every second, and between each action potential, your muscle membrane has to repolarize. Depolarizing agents work by not allowing the membrane to repolarize after depolarization, so you basically get one action potential, and after that, you can no longer kind of "recharge" your muscle to have it move again after that. Here's sort of an analogy. Let's say you are firing a gun at something and the firing of the gun is connected to the movement of a muscle. In order to keep the muscle moving, you have to keep firing the gun over and over, but each time you fire the gun, you have to reload it again to be able to fire it again and maintain movement. Depolarizing agents force the gun to be fired and then don't let you reload. It's almost like pulling the trigger and then holding it down and never letting go. Non-depolarizing agents just don't let you fire the gun at all. Overall, the main point is that neuromuscular blocking agents bind to acetylcholine receptors so acetylcholine can't. You need acetylcholine binding to acetylcholine receptors on your muscles to be able to move correctly. NMBs block the receptors and you don't move. Definitions Acetylcholine (ACh) - a neurotransmitter molecule with many functions. It is involved in learning, memory, and in this case, muscle movement. In muscle movement, when the action potential reaches the end of a motor neuron, acetylcholine is released from the end of the neuron (called the synaptic terminal), diffuses across the synaptic cleft, and binds to its receptors on the muscle cell membrane. Acetylcholine receptor (AChR) - A protein that binds to the molecule acetylcholine. There are multiple different types of acetylcholine receptors, but the one involved in voluntary movement called a nicotinic acetylcholine receptor. It is a channel protein, kind of like a tunnel that spans both sides of the muscle cell membrane, and it opens when acetylcholine binds to it. This allows sodium ions, which are usually in a higher concentration outside the muscle, to pass through channel and enter the inside of the muscle cell. Acetylcholinesterase (AChE) - An enzyme that breaks down acetylcholine so that it's not just out there binding to your receptors and causing muscle movement when you don't want to move. If this enzyme is inhibited, there will be an increased amount of acetylcholine in the neuromuscular junction, which can help counteract the effects of neuromuscular blocking agents. Depolarizing Agent - A neuromuscular blocking agent that binds to and opens acetylcholine receptors, causing an initial depolarization. It keeps the receptors open and does not allow the muscle to repolarize to be able to depolarize again and send another action potential after the first one. Succinylcholine (SCh) - The only depolarizing neuromuscular blocker used in the US. It has a very rapid onset (30 seconds to a minute) and a short duration (about 5 minutes). Because of its speed and short length, it is commonly used at the beginning of surgeries or in emergency situations to allow a patient to be quickly intubated. However, it also has some dangerous side effects, namely hyperkalemia (elevated potassium levels) and malignant hyperthermia. Non-Depolarizing Agent - A neuromuscular blocking agent that binds to and blocks nicotinic acetylcholine receptors on the motor end plate of skeletal muscles. Unlike acetylcholine, it does not cause the receptor to open when it binds, and it is not broken down by acetylcholinesterase. It just stays there and prevents acetylcholine from binding to and activating the receptor. When acetylcholine is unable to bind to its receptors, you don't move. d-Tubocurarine (dTC) - A non-depolarizing neuromuscular blocking agent and an active ingredient in curare, an arrow poison used by South American tribes to paralyze and kill their prey. It was used clinically for the first time in 1942 as a muscle relaxant during surgeries, and now has many derivatives which are still used in medicine today. Tubocurarine is a classic example of something that's been used as both poison and medicine. This molecule has really seen it all. Other things about NMBs: The progression goes from eyes to the facial muscles, the neck, extremities, limbs, abdominal, the glottis, and finally the intercostal muscles and diaphragm. If you see any sort of fictional thing where somebody is injected specifically with a neuromuscular blocking agent and they are unable to move but somehow can still look around with their eyes or blink or something, that's inaccurate. To preserve both eye movement and breathing, what you're looking for there is locked-in syndrome. NMBs don't do that in real life. Paralytic agents in movies often have the remarkable ability to bypass any important muscle required for a dramatic effect, such as the eyes, diaphragm, and occasionally muscles used for speech. In real life, neuromuscular blockers do not spare any voluntary muscles at all. Neuromuscular blocking molecules usually contain at least one quaternary ammonium (N+). This N+ is what makes it look like acetylcholine and bind to the acetylcholine receptor, because acetylcholine also has a N+ in its structure. The N+ also is what makes the molecules polar, the reason they don't cross the BBB. Dihydro-ß-erythroidine is a weird exception to this. It is a neuromuscular blocking agent without an N+, and strangely enough, when its N is made into an N+, it loses its neuromuscular blocking ability. Also, unlike other NMBs, since dihydro-ß-erythroidine has no positive charge on its nitrogen, it's non-polar enough to get absorbed through your digestive system and kill you if you eat it. Researchers are trying to make the perfect NMB. The ideal neuromuscular blocking agent is one that is nondepolarizing, of rapid onset (and relatively short duration), has no side effects, and does not depend on the liver and kidneys to break it down. Although no single NMB fits every single one of these requirements, several of them fit most of the requirements, and different NMBs can be selected based on the individual receiving them. The two big side effects that new NMBs are trying to avoid are histamine release and vagolytic effects (ex. tachycardia). NMBs are strange things in that they have both taken and saved lives. The molecules themselves and their mechanisms will never change. It's all about the way we use them. Category:Neuromuscular Blocking Agents